The development of aging and aging-related diseases involves body's progressive formation of oxidative stress and inflammation, a deleterious reaction that can be an important outcome of nutritional and energy imbalance. Conversely, aging across many species has been shown to be re-programmed by caloric restriction (CR);the underlying reactions include counteraction against oxidative stress by the FoxO and SIRT families. However, a large question has yet to be investigated: How nutrition connects with the aging process and what tissue(s) drive this connection. With the support of preliminary research that identified the role of hypothalamic IKK2/NF- :B in responding to nutrition and causing various whole-body physiological dysregulations, the long-term goal of this research is to address the fundamental question of how the master-switch pathway of metabolic inflammation, comprising I:B kinase-2 (IKK2) and the downstream nuclear transcription factor, NF-:B, in the hypothalamus mediates nutritional control of aging. Based on the established mouse models of this study, preliminary data were recently obtained to demonstrate: (1) aging is associated with chronic activation of IKK2/NF-:B and development of metabolic inflammation in the hypothalamus;(2) caloric restriction (CR) reduces aging-dependent IKK2/NF-:B activation and the related induction of metabolic inflammation in the hypothalamus;(3) Gene transfer-directed IKK2/NF-:B activation in the nutrition-sensing hypothalamic region, the mediobasal hypothalamus (MBH), suppresses several molecular markers (FoxOs and SIRTs) that underlie the anti-aging effects of CR;(4) Selective ablating IKK2 in nutrition-sensing neurons in the MBH de- accelerates aging and aging-associated health declines. Thus, this project hypothesizes that age-dependent activation of IKK2/NF-:B in the hypothalamus-particularly in the nutrition-sensing subregion and neuronal subpopulations-chronically promotes aging and aging-related physiological declines;suppressing IKK2/NF-:B in this region and in the related neurons can mimic and enhance the anti- aging effects of CR and represent a strategy for controlling aging-related disorders. The following 3 specific Aims will be performed to test this hypothesis are: 1) To profile hypothalamic IKK2/NF-:B activities in the normal and CR-modulated processes of aging;2) To test the action of IKK2/NF-:B on molecular markers of CR in the hypothalamus;3) To determine the role of hypothalamic IKK2/NF-:B in nutritional control of aging. The experiments of these Aims will orderly analyze aging-related molecles and physicology in a series of the established mouse models in which IKK2/NF-:B is activated or inhibited specifically in the nutrition-sensing hypothalamic region or cell subpopulations. This project represents the first of its kind in seeking to establish a brain-directed molecular and cellular basis that mediates the nutritional actions on aging. The successful completion of this project may also provide broad new strategies to combat aging-related diseases. PUBLIC HEALTH RELEVANCE: The development of aging and aging-related diseases involves body's progressive formation of oxidative stress and inflammation, a deleterious reaction that can be induced by calories from consumed food, and conversely, aging has been shown to be slowed down by caloric (food) restriction. Because the hypothalamus in the brain is the headquarters for sensing body's nutritional (calorie) status, and because an inflammatory pathway in the hypothalamus can respond to nutritional signals and affect hypothalamic functions, this project will investigate whether and how this inflammatory pathway in the hypothalamus mediates the nutritional actions on aging. Success of this study will advance our knowledge about how nutrition is involved in the development of aging and aging-related diseases, and provide broad new strategies to combat aging-related diseases.